We have already published our discovery that xanthones exhibit potent antimalarial activity, even against multi-drug resistant strains of Plasmodium falciparum. Based on our understanding of xanthone mode of action, we have developed a 2nd generation xanthone, 3,6-bis-omega-diethylaminoamyloxyxanthone (C5). C5 is approximately as potent as chloroquine, yet with equal activity against a panel of drug resistant strains. Herein, we propose to develop the 3 rd generation of xanthone anti-malarials, with a long-term view toward clinical trials. The steps toward this goal are: . Evaluate the in vivo efficacy of existing xanthone analogs. This will be investigated in the P. v. vinckei murine model of malaria. The possibility for acute toxicity of xanthones will be investigated in uninfected mice. . Evaluate the in vitro metabolism of C5 by microsomes. This will be investigated with both human and murine derived microsomes. . Optimize the drug structure beginning with C5 for both safety and antimalarial potency. This will be done in a process iterative between in vitro and in vivo testing, molecular modeling, pharmacokinetics, and spectroscopic evidence. . Synthesis and evaluation of 3rd generation compounds. The hallmark of these 3 rd generation xanthones will be improved safety and antimalarial potency. The 3 rd generation compounds will be inexpensive to produce, chemically and metabolically stable, and orally bioavailable. The mode of action of these xanthone-based antimalarial agents is inhibition of hemozoin formation via complexation of heme. Since heme is an immutable biomolecule, it is difficult to envision any simple mutation that could lead to resistance.